Language：English   Publishing type：Research paper (scientific journal)  

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, autosomal recessive neurodegenerative disorder caused by biallelic AAGGG/ACAGG repeat expansion (AAGGG-exp/ACAGG-exp) in RFC1. The recent identification of patients with CANVAS exhibiting compound heterozygosity for AAGGG-exp and truncating variants supports the loss-of-function of RFC1 in CANVAS patients. We investigated the pathological changes in two autopsied patients with CANVAS harboring biallelic ACAGG-exp and AAGGG-exp. RNA fluorescence in situ hybridization of the two patients revealed CCTGT- and CCCTT-containing RNA foci, respectively, in neuronal nuclei of tissues with neuronal loss. Our findings suggest that RNA toxicity may be involved in the pathogenesis of CANVAS. This article is protected by copyright. All rights reserved.

DOI： 10.1002/ana.26848

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

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Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

In amyotrophic lateral sclerosis (ALS), neurodegeneration is characterized by distal axonopathy that begins at the distal axons, including the neuromuscular junctions, and progresses proximally in a “dying back” manner prior to the degeneration of cell bodies. However, the molecular mechanism for distal axonopathy in ALS has not been fully addressed. Semaphorin 3A (Sema3A), a repulsive axon guidance molecule that phosphorylates collapsin response mediator proteins (CRMPs), is known to be highly expressed in Schwann cells near distal axons in a mouse model of ALS. To clarify the involvement of Sema3A–CRMP signaling in the axonal pathogenesis of ALS, we investigated the expression of phosphorylated CRMP1 (pCRMP1) in the spinal cords of 35 patients with sporadic ALS and seven disease controls. In ALS patients, we found that pCRMP1 accumulated in the proximal axons and co-localized with phosphorylated neurofilaments (pNFs), which are a major protein constituent of spheroids. Interestingly, the pCRMP1:pNF ratio of the fluorescence signal in spheroid immunostaining was inversely correlated with disease duration in 18 evaluable ALS patients, indicating that the accumulation of pCRMP1 may precede that of pNFs in spheroids or promote ALS progression. In addition, overexpression of a phospho-mimicking CRMP1 mutant inhibited axonal outgrowth in Neuro2A cells. Taken together, these results indicate that pCRMP1 may be involved in the pathogenesis of axonopathy in ALS, leading to spheroid formation through the proximal progression of axonopathy.

DOI： 10.3389/fneur.2022.994676

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Language：English   Publishing type：Research paper (scientific journal)  

A 39-year-old man exhibited ocular flutter and cerebellar ataxia following a subacute disturbance of consciousness and partial seizure. He was diagnosed with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy by tissue- and cell-based antibody assays. Brain single-photon emission computed tomography detected a significant increase in blood flow in the fastigial nucleus, a critical region for eye saccade control. Immunotherapies diminished the ocular flutter and reduced hyperperfusion in the fastigial nucleus. This case suggests that autoimmune GFAP astrocytopathy can cause ocular flutter and provides strong imaging evidence supporting the hypothesis that ocular flutter is caused by hyperactivity or disinhibition of the fastigial nucleus.

DOI： 10.1016/j.clineuro.2022.107307

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.neures.2022.08.003

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Language：English   Publishing type：Research paper (scientific journal)  

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1G93A mice using Crmp1S522A (Ser522→Ala) knockin (Crmp1ki/ki ) mice in which the S522 phosphorylation site was abolished and Crmp1 knockout (Crmp1 -/-) mice, respectively. Crmp1ki/ki/SOD1G93A mice showed longer latency to fall in a rotarod test while Crmp1-/-/SOD1G93A mice showed shorter latency compared with SOD1G93A mice. Survival was prolonged in Crmp1ki/ki/SOD1G93A mice but not in Crmp1-/-/SOD1G93A mice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions were comparatively well-preserved in Crmp1ki/ki/SOD1G93A mice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects in Crmp1ki/ki/SOD1G93A and Crmp1-/-/SOD1G93A mice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.Significance StatementCollapsin response mediator protein 1 (CRMP1) is an intracellular molecule that mediates semaphorin 3A (Sema3A) signaling. Phosphoproteomic analysis showed that the Semaphorin Neuronal Repulsive Signaling Pathway, which includes Crmp1 phosphorylation at Ser522, is upregulated in SOD1G93A mice that serve as a model of amyotrophic lateral sclerosis (ALS). While deleting both copies of the Crmp1 gene (Crmp1-/- ) leads to deterioration of motor function in SOD1G93A mice, phospho-null Crmp1 (Crmp1ki/ki ) improves motor function while preventing motor neuron loss and denervation of neuromuscular junctions. Among the Sema3A-mediated axon guidance pathways, we propose that CRMP1 phosphorylation is a potential therapeutic target for ALS.

DOI： 10.1523/ENEURO.0133-22.2022

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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OBJECTIVE: To determine whether autonomic dysfunction in neurosarcoidosis is associated with anti-ganglionic acetylcholine receptor (gAChR) antibodies, which are detected in autoimmune autonomic ganglionopathy. METHODS: We retrospectively extracted cases of sarcoidosis from 1787 serum samples of 1,381 patients between 2012 and 2018. Anti-gAChR antibodies against the α3 and β4 subunit were measured by luciferase immunoprecipitation to confirm the clinical features of each case. We summarized literature reviews of neurosarcoidosis with severe dysautonomia to identify relevant clinical features and outcomes. RESULTS: We extracted three new cases of neurosarcoidosis with severe dysautonomia, among which two were positive for anti-gAChR antibodies: Case 1 was positive for antibodies against the β4 subunit, and Case 2 was positive for antibodies against both the α3 and β4 subunits. We reviewed the cases of 15 patients with neurosarcoidosis and severe dysautonomia, including the three cases presented herein. Orthostatic hypotension and orthostatic intolerance were the most common symptoms. Among the various types of neuropathy, small fiber neuropathy (SFN) was the most prevalent, with seven of nine cases exhibiting definite SFN. Six of eight cases had impaired postganglionic fibers, of which the present three cases revealed abnormality of 123I-MIBG myocardial scintigraphy. Of the 11 cases, 10 were responsive to immunotherapy, except one seropositive case (Case 2). CONCLUSIONS: The presence of gAChR antibodies may constitute one of the mechanisms by which dysautonomia arises in neurosarcoidosis.

DOI： 10.1007/s00415-021-10551-4

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Intracellular aggregates are a common pathological hallmark of neurodegenerative diseases such as polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple system atrophy (MSA). Aggregates are mainly formed by aberrant disease-specific proteins and are accompanied by accumulation of other aggregate-interacting proteins. Although aggregate-interacting proteins have been considered to modulate the formation of aggregates and to be involved in molecular mechanisms of disease progression, the components of aggregate-interacting proteins remain unknown. In this study, we showed that small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) is an aggregate-interacting protein in neurodegenerative diseases. Immunohistochemistry showed that SGTA interacted with intracellular aggregates in Huntington disease (HD) cell models and neurons of HD model mice. We also revealed that SGTA colocalized with intracellular aggregates in postmortem brains of patients with polyQ diseases including spinocerebellar ataxia (SCA)1, SCA2, SCA3, and dentatorubral-pallidoluysian atrophy. In addition, SGTA colocalized with glial cytoplasmic inclusions in the brains of MSA patients, whereas no accumulation of SGTA was observed in neurons of PD and ALS patients. In vitro study showed that SGTA bound to polyQ aggregates through its C-terminal domain and SGTA overexpression reduced intracellular aggregates. These results suggest that SGTA may play a role in the formation of aggregates and may act as potential modifier of molecular pathological mechanisms of polyQ diseases and MSA.

DOI： 10.1186/s13041-021-00770-1

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INTRODUCTION: Mild cognitive dysfunction has been implicated in a number of psychiatric diseases and affects social functioning. Although clinical criteria were recently proposed for autoimmune psychosis (AP), biomarkers have not yet been established for the severity and prognosis of cognitive dysfunction. We herein investigated the relationships between 3 types of serum antibodies and cognitive dysfunction in chronic psychiatric patients suspected of AP. METHODS: We included 31 patients suspected of AP and obtained information on their clinical characteristics. Three types of autoantibodies (the anti-N-methyl-D-aspartate receptor (anti-NMDAR Ab), anti-N-terminal of GluN1 (anti-GluN1-NT Ab), and anti-thyroid antibodies) were evaluated in serum. Cognitive function was assessed using Wechsler Adult Intelligence Scale-III. We examined the relationships between serum autoantibodies and cognitive dysfunction in patients using multiple regression models. RESULTS: Serum titers of anti-GluN1-NT Ab significantly contributed to the estimated score of working memory (B= -55.85, β= -0.46, p= 0.01), while no correlation was observed between the other 2 types of antibodies and cognitive function. CONCLUSIONS: The present results indicate the potential of serum anti-GluN1-NT Ab as a biomarker for the severity and prognosis of cognitive dysfunction underlying various psychiatric symptoms in patients with AP. The pathological significance of anti-GluN1-NT Ab needs to be verified in future studies.

DOI： 10.1016/j.neulet.2020.135588

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Language：Japanese   Publisher：(一社)日本神経学会  

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RNA polymerase III (POLR3)-related leukodystrophy is an autosomal recessive form of leukodystrophy caused by homozygous or compound heterozygous mutations of the RNA polymerase III subunit genes, including subunit A (POLR3A). With respect to the manifestation triad, hypomyelination, hypodontia, and hypogonadotropic hypogonadism, it is also known as 4H leukodystrophy. Here, we report a 41-year-old woman of POLR3-related leukodystrophy by carrying compound heterozygous pathogenic variants of c.2554A>G (p.M852V) and c.2668G>T (p.V890F) in the POLR3A gene. She was amenorrheic and became a wheelchair user from the age of 15 years and suffered from multiple episodes of pathologic fractures, starting with a subtrochanteric fracture of the right femur after a tonic seizure at age 30 years. Head magnetic resonance imaging demonstrated hypomyelination and atrophies of the cerebellum, brainstem, and corpus callosum. Laboratory examination revealed a marked decrease of gonadotropins and estrogen, low bone density, and high bone resorption markers. Administration of anti-receptor activator of nuclear factor kappa-B ligand monoclonal antibody restored bone resorption markers to a normal level and prevented further pathological bone fractures. Our case emphasizes that osteoporosis should be recognized as a potential but serious complication in POLR3-related leukodystrophy. It may be feasible to prevent pathologic fractures by intensive osteoporosis therapy after endocrinological examinations and evaluation of bone metabolism.

DOI： 10.3389/fneur.2021.622355

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We herein report a 33-year-old woman who was an asymptomatic hepatitis B virus (HBV) carrier and presented with distal muscle weakness in the legs and asymmetrical paresthesia in the distal extremities. A nerve biopsy specimen revealed fibrinoid necrosis associated with inflammatory infiltration in the perineural space, and deposition of hepatitis B core antigen and C4d complement was detected in the vascular endothelial cells as well as around the vessels. She was diagnosed with HBV-related vasculitic neuropathy and treated with intravenous immunoglobulin (IVIG). Her symptoms completely subsided after eight weeks. Vasculitic neuropathy rarely develops in the chronic inactive stages of HBV infection. This is the first report of an HBV-inactive carrier with vasculitic neuropathy successfully treated with IVIG.

DOI： 10.2169/internalmedicine.4498-20

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Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 78-year-old woman with bilateral fungal sinusitis, which resulted in right orbital apex syndrome, underwent endoscopic sinus surgery and optic nerve decompression. Two months after the operation, she complained of anxiety and insomnia. Head CT showed subdural hematoma-like effusion and burr hole drainage was conducted. The collected fluid was not hematoma, but bloody, xanthochromic effusion with no pathogenic bacteria. Ten days later, she underwent drainage and dural biopsy after craniotomy because of relapse of subdural hygroma and progression of hypertrophic pachymeningitis associated with aggravation of psychiatric symptoms. A sample of the dura mater showed dense fibrosis with thickening, and Pseudomonas aeruginosa (P. aeruginosa) was detected by culture. Although otitis or sinusitis secondary to P. aeruginosa infection has been reported as a leading cause of infectious pachymeningitis, psychiatric symptoms alone and concomitant refractory subdural hygroma are atypical and unreported manifestations. In patients with pachymeningitis and a history of transnasal endoscopic surgery, P. aeruginosa infection should be considered, irrespective of an atypical clinical course and negative blood or fluid culture. Additionally, dural biopsy might help in detection of pathogenic bacteria.

DOI： 10.5692/clinicalneurol.60.cn-001418

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Language：Japanese   Publisher：(一社)日本神経学会  

78歳女性.右眼窩先端症候群・両側真菌性副鼻腔炎に対する内視鏡下右視神経管開放術・副鼻腔手術施行2ヶ月後,精神症状,異常行動が出現した.当初右慢性硬膜下血腫の診断であったが,穿頭ドレナージ術により高蛋白の滲出液貯留が確認された.原因は不明であり,10日後に液体再貯留と硬膜肥厚を認めた.硬膜生検による組織培養にて初めて緑膿菌が検出され,レボフロキサシンの内服により軽快した.局所の緑膿菌感染に続発する肥厚性硬膜炎は,疼痛を初発症状とし進行すると脳神経麻痺などを呈する経過が典型的であるが,疼痛なしに硬膜下水腫を伴い亜急性の精神症状でのみ発症した症例は報告されておらず,本例は稀な症例と考えられた.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01550&link_issn=&doc_id=20200820280010&doc_link_id=130007885759&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007885759&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

INTRODUCTION: Variants of CACNA1G, which encodes CaV3.1, have been reported to be associated with various neurological disorders. METHODS: Whole-exome sequencing of genomic DNA from 348 Japanese patients with neurodevelopmental disorders and their parents was conducted, and de novo variants of CACNA1G were extracted. The electrophysiological properties of each mutant channel were investigated by voltage-clamp and current-clamp analyses of HEK293T cells overexpressing these channels. RESULTS: Two patients diagnosed with Rett syndrome and West syndrome were found to have known pathological CACNA1G mutations reported in cerebellar ataxia cohorts: c.2881G > A, p.Ala961Thr and c.4591A > G, p.Met1531Val, respectively. One patient with Lennox-Gastaut syndrome was revealed to harbor a previously unreported heterozygous variant: c.3817A > T, p.Ile1273Phe. Clinical symptoms of the two patients with known mutations included severe developmental delay without acquisition of the ability to walk independently. The patient with a potentially novel mutation showed developmental delay, intractable seizures, and mild cerebral atrophy on MRI, but the severity of symptoms was milder than in the former two cases. Electrophysiological study using HEK293T cells demonstrated significant changes of T-type Ca2+ currents by p.Ala961Thr and p.Met1531Val SNVs, which were likely to enhance oscillation of membrane potential at low frequencies. In contrast, p.Ile1273Phe showed no significant effects in our electrophysiological evaluations, with its pathogenesis remaining undetermined. CONCLUSION: De novo variants of CACNA1G explain some neurodevelopmental disorders. Our study further provides information to understand the genotype-phenotype correlations of patients with CACNA1G mutations.

DOI： 10.1016/j.jns.2020.117047

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DOI： 10.1002/ana.25819

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It remains controversial whether circulating monocytes expressing CCR2 infiltrate the central nervous system (CNS) and contribute to pathogenicity of amyotrophic lateral sclerosis (ALS). A previous report used conventional immunohistochemistry to show that CCR2 is exclusively expressed by astrocytes, but not infiltrating monocytes/microglia or neurons, in the spinal cords of ALS model mice. In this study, we assessed the cellular distribution of CCR2 in the CNS of ALS mice using CCR2-reporter mice (Ccr2rfp/+-Cx3cr1gfp/+-SOD1G93A Tg mice), a more sophisticated method for directly detecting the distribution of CCR2 protein. We found that infiltration of CCR2+ monocytes in the lumbar spinal cord increased over the course of disease progression. Moreover, from the middle stage of disease, CCR2 was partially distributed in microglia and neurons, but not astrocytes, in striking contrast to the previous findings. These novel observations suggested that CCR2+ monocyte infiltration leads to CNS environmental deterioration due to toxic conversion of microglia and neurons, creating a vicious cycle of neuroinflammation and leading to acceleration of ALS pathology. Our findings also show that this reporter mouse is a useful and powerful tool for obtaining new insights into the pathomechanisms of ALS.

DOI： 10.1186/s13041-020-00607-3

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Language：Japanese   Publisher：(一社)日本神経学会  

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Recently, a recessively inherited intronic repeat expansion in replication factor C1 (RFC1) was identified in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Here, we describe a Japanese case of genetically confirmed CANVAS with autonomic failure and auditory hallucination. The case showed impaired uptake of iodine-123-metaiodobenzylguanidine and 123I-ioflupane in the cardiac sympathetic nerve and dopaminergic neurons, respectively, by single-photon emission computed tomography. Long-read sequencing identified biallelic pathogenic (AAGGG)n nucleotide repeat expansion in RFC1 and heterozygous benign (TAAAA)n and (TAGAA)n expansions in brain expressed, associated with NEDD4 (BEAN1). Enrichment of the repeat regions in RFC1 and BEAN1 using a Cas9-mediated system clearly distinguished between pathogenic and benign repeat expansions. The haplotype around RFC1 indicated that the (AAGGG)n expansion in our case was on the same ancestral allele as that of European cases. Thus, long-read sequencing facilitates precise genetic diagnosis of diseases with complex repeat structures and various expansions.

DOI： 10.1038/s10038-020-0733-y

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Chronic tonsillitis has been attracted attention as a source of abnormal immune responses and a possible trigger of autoimmune diseases such as IgA nephritis, IgA vasculitis, palmoplantar pustulosis, psoriasis, rheumatoid arthritis, Behçet's disease, and myositis. Here we present the first report of anti-signal recognition particle antibody-associated necrotizing myopathy (anti-SRP myopathy) with IgA nephropathy and chronic tonsillitis in which the therapeutic response to intravenous immunoglobulin (IVIG) treatment was dramatically improved after tonsillectomy and accompanied by a rapid increase in ΔIgG, defined as the change in serum IgG levels 2 weeks after the start of IVIG treatment relative to pre-treatment levels. Moreover, serum anti-SRP antibody titers became undetectable after tonsillectomy even though the resected tonsils did not produce anti-SRP antibodies. Tonsillectomy should be considered when chronic tonsillitis is observed in patients with autoimmune diseases showing poor response to treatment, including anti-SRP myopathy.

DOI： 10.3389/fimmu.2020.595480

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Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. In this study, we analyzed 101 Japanese patients with genetically unresolved adult leukoencephalopathy using whole-exome sequencing and repeat-primed polymerase chain reaction for detecting GGC expansion in NOTCH2NLC. NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease. We found 12 patients with GGC expansion in NOTCH2NLC as the most frequent cause of adult leukoencephalopathy followed by NOTCH3 variants in our cohort. Furthermore, we found 1 case with de novo GGC expansion, which might explain the underlying pathogenesis of sporadic cases. ANN NEUROL 2019;86:962-968.

DOI： 10.1002/ana.25586

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DOI： 10.1212/CPJ.0000000000000599

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Exosomes contain many proteins associated with neurodegenerative diseases. To identify new candidate biomarkers and proteins associated with amyotrophic lateral sclerosis (ALS), we performed liquid chromatography-tandem mass spectrometry proteomic analysis of exosome-enriched fractions isolated from cerebrospinal fluid (CSF) of sporadic ALS patients using gel filtration chromatography. Proteomic data revealed that three proteins were increased and 11 proteins were decreased in ALS patients. The protein with the greatest increase in exosome-enriched fractions of CSF derived from ALS was novel INHAT repressor (NIR), which is closely associated with nucleolar function. By immunohistochemical analysis, we found that NIR was reduced in the nucleus of motor neurons in ALS patients. Our results demonstrate the potential utility of our methodology for proteomic analysis of CSF exosomes and suggest that nucleolar stress might play a role in sporadic ALS pathogenesis through the dysfunction of NIR.

DOI： 10.1016/j.neures.2019.10.010

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Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

DOI： 10.1016/j.nbd.2019.104516

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A 24-year-old Japanese man exhibited slowly progressive gait disturbance from childhood to young adulthood. Physical and physiological examinations showed the involvement of both upper and lower motor neurons, fulfilling the diagnostic criteria for amyotrophic lateral sclerosis (ALS). Mild cognitive impairment and subclinical sensory involvement were also observed. A genetic analysis revealed novel compound heterozygous mutations, c.767C>T (p.Thr256Ile) and c.800A>G (p.Asp267Gly), in the vaccinia-related kinase 1 gene (VRK1). This is the first report of a Japanese patient with a motor neuron disease phenotype caused by VRK1 mutations. This diagnosis should be considered in atypical cases of juvenile-onset and slowly progressive types of motor neuron disease.

DOI： 10.2169/internalmedicine.2126-18

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Language：Japanese   Publisher：日本神経感染症学会  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom‐designed gene panel. We selected 55 leukoencephalopathy‐related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.

DOI： 10.1111/cge.13371

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cge.13371

Language：Japanese   Publisher：(一社)日本神経学会  

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Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.

DOI： 10.1038/s10038-017-0408-5

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BACKGROUND: Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral olfactory tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. METHODS: CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. RESULTS: Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. CONCLUSIONS: CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases.

DOI： 10.1186/s12974-018-1084-x

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Language：English   Publishing type：Research paper (scientific journal)  

Mutations in the MATR3 gene have been identified as a cause of familial amyotrophic lateral sclerosis, but involvement of the matrin 3 (MATR3) protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. We immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsy specimens. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns: mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases. MATR3-containing neuronal cytoplasmic inclusions (NCIs) were observed in 60% of SALS cases. Most motor neurons with MATR3-positive NCIs exhibited a mild nuclear staining pattern. Although 16.8% of NCIs positive for transactivating response region DNA-binding protein 43 (TDP-43) were estimated as double-labeled by MATR3, no MATR3-positive or TDP-43-negative NCIs were observed. Although a previous study found that MATR3-positive NCIs are present only in cases with C9orf72 hexanucleotide repeat expansion, ubiquitin-positive granular NCIs were not observed in the cerebellum, which have been reported as specific to C9orf72-related ALS. Six ALS cases were confirmed to be negative for the GGGGCC hexanucleotide. Our results reveal that MATR3 is a component of TDP-43-positive NCIs in motor neurons, even in SALS, and indicate the broader involvement of MATR3 in ALS pathology and the heterogeneity of TDP-43-positive NCIs.

DOI： 10.1016/j.ajpath.2017.10.007

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Recent new sequencing techniques allow the identification of novel responsible genes for autosomal recessive spinocerebellar ataxias (ARCAs). However, the same phenotypes are sometimes attributed to the different responsible genes in ARCAs. On the contrary, the same responsible genes may cause heterogeneous phenotypes with respect to the age at onset, symptoms, and the severity of the disease progression. In addition, it is an important issue to clarify whether the gene mutations identified in Caucasian patients with infantile-onset ARCAs are also observed in Japanese patients with adult-onset ARCAs. In this article we review the characteristics of several ARCAs, the existence of which has been recently identified or confirmed in Japan.

DOI： 10.5692/clinicalneurol.cn-000879

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Language：Japanese   Publisher：(一社)日本神経学会  

近年のゲノムシークエンス技術の進歩により、常染色体劣性遺伝性脊髄小脳変性症の新たな責任遺伝子が次々と明らかになってきている。しかし、同じような表現型を示していても責任遺伝子が全く異なる場合や、逆に同じ責任遺伝子であっても発症年齢、症状、疾患進行が大きく異なる場合があり、診断は容易ではない。また、欧米の特に小児期発症例において同定された遺伝子変異が、本邦の成人発症例においてもみられるのかどうかは、今後も引き続き検討が必要な課題である。本稿では、主として近年本邦でも存在が確認された比較的まれと考えられる劣性遺伝性脊髄小脳変性症について概説する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01550&link_issn=&doc_id=20160728260001&doc_link_id=130005158857&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130005158857&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Language：English   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Mitochondrial complex III (CIII) deficiency comprises a group of complex and heterogeneous genetic disorders. TTC19 mutations constitute a rare cause of CIII deficiency and are associated with neurological disorders in childhood and adulthood. Herein, we describe a 27-year-old Japanese man with cerebellar ataxia, spastic paraparesis, loss of deep sensation, mild frontal lobe dysfunction and transient psychiatric symptoms. Brain magnetic resonance imaging showed cerebellar atrophy and bilateral high-intensity signals in the inferior olives and regions adjacent to periaqueductal gray matter, on T2-weighted images. On whole-exome sequencing, we detected a novel homozygous frameshift mutation c.157_158dup [p.Pro54Alafs* 48] in TTC19. Mitochondrial enzyme assays confirmed mild impairment of CIII enzymatic activity in lymphoblasts, which was consistent with TTC19-related CIII deficiency. His symptoms and radiological findings demonstrated an early stage or mild form of this disease, and further clarify the characteristics of patients with rare TTC19 mutations.

DOI： 10.1038/jhg.2015.7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

DOI： 10.1016/j.psym.2013.07.001

Scopus

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.psym.2013.07.001

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本脳卒中学会  

症例は79歳男性。糖尿病で内服加療を行っていたが、突然発症の右不全片麻痺を来し当院に救急搬送された。頭部MRI拡散強調画像で左内包後脚に高信号を認めた。血糖が30mg/dlと著明に低下しており50%グルコースを静注したところ症状は速やかに消失し、片麻痺の原因は低血糖によるものと考えられた。患者は過去にも低血糖による内包後脚のMRI異常信号を呈し、右不全片麻痺を発症していた。低血糖発作による脳卒中様の片麻痺は過去にも報告がみられるが、同一部位に繰り返しMRI異常信号を認めた例はこれまでにない。内包後脚が低血糖への脆弱性が高い脳組織の一つであることが示された。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J01786&link_issn=&doc_id=20141003400010&doc_link_id=%2Fdh3strok%2F2014%2F003605%2F010%2F0370-0373%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdh3strok%2F2014%2F003605%2F010%2F0370-0373%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

In neonates, the stress of social isolation can alter developing neural circuits and cause mental illness. However, the molecular and cellular bases for these effects are poorly understood. Experience-driven synaptic AMPA receptor delivery is crucial for circuit organisation during development. In the rat, whisker experience drives the delivery of glutamate receptor subunit 4 (GluA4) but not glutamate receptor subunit 1 (GluA1) to layer 42/3 pyramidal synapses in the barrel cortex during postnatal day (P)810, whereas GluA1 but not GluA4 is delivered to these synapses during P1214. We recently reported that early social isolation disrupts experience-driven GluA1 delivery to layer 42/3 pyramidal synapses during P1214. Here, we report that neonatal isolation affects even earlier stages of development by preventing experience-dependent synaptic GluA4 delivery. Thus, social isolation severely affects synaptic maturation throughout early postnatal development.

DOI： 10.1111/ejn.12188

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Language：English  

Patients with anti-thyroid antibodies (ATAs) present various kinds of psychiatric conditions. When these psychiatric patients with ATAs (PPATs) show responsiveness to immunotherapy, they are frequently diagnosed with a diffuse progressive type of Hashimoto's encephalopathy (HE). Anti-glutamate receptor ɛ2 subunit (GluRɛ2) antibodies have previously been reported in HE patients. However, it is unclear whether there is any relationship between PPATs, including HE patients, and anti-GluRɛ2 antibodies. We investigated anti-GluRɛ2 antibodies in the serum and cerebrospinal fluid (CSF) of 15 PPATs, and we compared the results with those of 11 patients with neuropsychiatric systemic lupus erythematosus (NPSLE), an anti-glutamate receptor antibody-related disease. We then compared the neuropsychiatric symptoms between the PPATs with and without anti-GluRɛ2 antibodies. The prevalence of anti-GluRɛ2 antibodies was significantly higher in the CSF than in the serum of PPATs (41.7% versus 6.7%; p=0.040). The prevalence of anti-GluRɛ2 antibodies was slightly higher in the CSF of PPATs than NPSLE patients. PPAT-GluR(+)s showed a significantly higher prevalence of emotional instability (100%

DOI： 10.1016/j.neulet.2012.10.060

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Patients with anti-thyroid antibodies (ATAs) present various kinds of psychiatric conditions. When these psychiatric patients with ATAs (PPATs) show responsiveness to immunotherapy, they are frequently diagnosed with a diffuse progressive type of Hashimoto's encephalopathy (HE). Anti-glutamate receptor epsilon 2 subunit (GluR epsilon 2) antibodies have previously been reported in HE patients. However, it is unclear whether there is any relationship between PPATs, including HE patients, and anti-GluR epsilon 2 antibodies. We investigated anti-GluR epsilon 2 antibodies in the serum and cerebrospinal fluid (CSF) of 15 PPATs, and we compared the results with those of 11 patients with neuropsychiatric systemic lupus erythematosus (NPSLE), an anti-glutamate receptor antibody-related disease. We then compared the neuropsychiatric symptoms between the PPATs with and without anti-GluR epsilon 2 antibodies. The prevalence of anti-GluR epsilon 2 antibodies was significantly higher in the CSF than in the serum of PPATs (41.7% versus 6.7%; p = 0.040). The prevalence of anti-GluR epsilon 2 antibodies was slightly higher in the CSF of PPATs than NPSLE patients. PPAT-GluR(+)s showed a significantly higher prevalence of emotional instability (100% versus 33.3%; p = 0.03) and also showed a significantly lower prevalence of delusions (0% versus 100%; p = 0.001) and hallucinations (17% versus 83%; p = 0.038) than PPAT-GluR(-)s. Our results suggest that anti-GluR epsilon 2 antibodies may be associated with the neuropsychiatric manifestation of PPATs. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2012.10.060

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

During early postnatal brain development, experience-driven delivery of AMPA receptors to synapses participates in the initial organization of conical function. By combining virus-mediated in vivo gene delivery with in vitro whole cell recordings, we identified a subunit-specific developmental program of experience-driven AMPA receptor delivery to synapses in rat barrel cortex. We expressed green fluorescent protein (GFP)-tagged AMPA receptors (GFP-GluR1, or GFP-GluR4) into layer 2/3 pyramidal neurons at two distinct developmental periods, postnatal day (P)8-P10 and P12-P14. Two days after viral infection, acute brain slices were prepared, and synaptic transmission from layer 4 to layer 2/3 was analyzed by whole cell recordings. We found that whisker experience drives GluR4 but not GluR1 into these synapses early in postnatal development (P8-1310). However, at P12-14, GluR1 but not GluR4 is delivered into synapses by whisker experience. This precise developmental plan suggests unique plasticity properties endowed in different AMPA receptor subunits which shape the initial experience-driven organization of cortical function. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2011.11.033

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J01205&link_issn=&doc_id=20100621240163&doc_link_id=%2Fag6niria%2F2010%2F0068s6%2F164%2F0629-0632%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2010%2F0068s6%2F164%2F0629-0632%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：日本自律神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本高次脳機能障害学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.99.1656

CiNii Books

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Language：Japanese   Publisher：日本自律神経学会  

パーキンソン病(PD)、多系統萎縮症(MSA)に薬物点眼検査を施行し、疾患間に相違ないか検討した。薬物点眼試験を施行したPD 24例、オリーブ橋小脳萎縮症(OPCA)33例、線状体黒質変性症(SND)14例、シャイ・ドレーガー症候群(SDS)5例を対象とした。点眼薬は1.25%エピネフリンまたは1%フェニレフリン(E・P)、5%チラミン(T)、および5%コカイン(C)を使用した。E・Pの過剰散瞳は、PD 22例中10例.OPCA 32例中16例、SND 15例中7例、SDS 5例中3例で、節後性障害でTの反応低下を伴う例はPD 3例、OPCA 2例、SND 1例、SDS 1例、Cでの反応低下例はPD 5例、OPCA 7例、SND 5例、SDS 4例であった。瞳孔反応異常は他の自律神経障害と無関係で、他の障害に先行する症例も認めた。点眼試験は、鑑別には有用ではなかった。

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